Multipotent mesenchymal stromal cells (MSCs) have potential therapeutic benefit in many diseases including neurological diseases and injury. MSC-based therapies enhance recovery from stroke. We have previously demonstrated that exogenously administered MSCs interact with neural cells, increase the production of neurites, reduce expression of axonal inhibitory molecules and stimulate the production of growth and plasticity positive factors in neural cells, which promote neurorestoration and recovery of neurological function. However, it is unknown how MSCs interact with neural cells, alter their protein expression, and thereby promote functional recovery. In the present proposal, we provide fundamental and novel mechanistic insight into how cell-based therapies promote recovery. MicroRNAs (miRNAs) act as master switches regulating the translation of many genes, and exosomes are membrane vesicles, 40-100nm in diameter, that are secreted by a wide range of cell types. We propose that MSCs increase specific miRNA levels in neural cells via exosomes, which subsequently stimulate neurite outgrowth and functional recovery. Based on our preliminary data, we will primarily focus on miR-133b, as an important target miRNA. Two specific aims are proposed. Aim 1: To investigate whether exosomes primarily mediate cell-cell communication by direct transfer of miR-133b to neural cells and/or indirectly by stimulating miR-133b expression in neural cells, which subsequently promote neurite outgrowth and functional recovery after stroke. Aim 2: To investigate the mechanisms by which miR-133b promotes neurite remodeling after treatment of stroke with MSCs. This study opens up important and novel ways to elucidate how exogenously administered cells communicate with and alter neural cells to activate restorative events. Confirming our hypothesis represents a major leap forward in our understanding of cell-cell communication and will lead to novel ways to augment brain recovery.